The intestinal microbiota programs diurnal rhythms in host metabolism through histone deacetylase 3

Science. 2019 Sep 27;365(6460):1428-1434. doi: 10.1126/science.aaw3134.

Abstract

Circadian rhythmicity is a defining feature of mammalian metabolism that synchronizes metabolic processes to day-night light cycles. Here, we show that the intestinal microbiota programs diurnal metabolic rhythms in the mouse small intestine through histone deacetylase 3 (HDAC3). The microbiota induced expression of intestinal epithelial HDAC3, which was recruited rhythmically to chromatin, and produced synchronized diurnal oscillations in histone acetylation, metabolic gene expression, and nutrient uptake. HDAC3 also functioned noncanonically to coactivate estrogen-related receptor α, inducing microbiota-dependent rhythmic transcription of the lipid transporter gene Cd36 and promoting lipid absorption and diet-induced obesity. Our findings reveal that HDAC3 integrates microbial and circadian cues for regulation of diurnal metabolic rhythms and pinpoint a key mechanism by which the microbiota controls host metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • CD36 Antigens / metabolism
  • Chromatin / metabolism
  • Circadian Rhythm*
  • Colon
  • Diet, High-Fat
  • Epithelial Cells / metabolism*
  • Gastrointestinal Microbiome*
  • Germ-Free Life
  • Histone Deacetylases / metabolism*
  • Intestine, Small / cytology
  • Intestine, Small / metabolism*
  • Jet Lag Syndrome
  • Lipid Metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / metabolism
  • Receptors, Estrogen / metabolism

Substances

  • CD36 Antigens
  • Chromatin
  • ERRalpha estrogen-related receptor
  • Receptors, Estrogen
  • Histone Deacetylases
  • histone deacetylase 3